The present invention concerns new phospholipid derivatives of nucleosides of the general formula I 
in which
R1 denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 9-14 carbon atoms which can optionally be substituted once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkyl-mercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl groups,
R2 represents a straight-chained or branched, saturated or unsaturated aliphatic residue with 8-12 carbon atoms which can be substituted once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkyl-mercapto, C1-C6 alkoxycarbonyl or C1-C6 alkylsulfonyl groups,
m equals 2 or 3,
A can represents a methylene group or an oxygen,
Nuc can be a nucleoside or a residue derived from a nucleoside derivative,
as well as tautomers thereof and their physiologically tolerated salts of inorganic and organic acids and bases, and pharmaceutical preparations containing these compounds.
Since the compounds of the general formula I contain asymmetric carbon atoms, the present invention also concerns all optically active forms and racemic mixtures of these compounds.
Numerous nucleoside diphosphate diacylglycerols and their production are described in the literature. The synthesis of corresponding derivatives of AZT, DDC and d2T is described in Biochim. Biophys. Acta 1165, 45 (1992) and J. Lipid Res. 33, 1211 (1992).
Biochem. Biophys. Acta 1084, 307 (1991) and 1086, 99 (1991) shows the release of the nucleoside monophosphate by mitochondrial enzyme activity from rat liver.
The protein-induced intermembrane transfer of antiviral derivatives as well as their synthesis is described by Biochemistry 31, 5912 (1992) and J. Biol. Chem. 265, 6112 (1990).
The antitumoural action of ara-C diphosphate derivatives with ether and thioether lipids in the SN1 positions is described in LIPIDS 26, 1437 (1991), Drugs of the Future 15, 245 (1990), Exp. Hematol. 17, 364 (1989), J. Med. Chem. 33, 1380 (1990) and Cancer Res. 50, 4401 (1990).
EP 0 376 518 demonstrates the antineoplastic properties of 2xe2x80x2-deoxy-2xe2x80x2,2xe2x80x2-difluoronucleoside derivatives and J. Med. Chem. 25, 1322 (1982) and 31, 1793 (1988) give information on the synthesis and antitumoural action of ara-C-5xe2x80x2-diphosphate diacylglycerols.
The applications DD-290-197 and EP 0 432 183 describe the synthesis of cytidine-5xe2x80x2-diphosphate-1-0-alkyl-glycerol with antitumoural action and EP 0 355 016 describes the synthesis of corresponding diphosphate glycerols.
The production of ara-C-5xe2x80x2-diphosphate-1-O-octadecyl-2-O-palmitoylglycerol is described in DE 35 43 346 and d2T-5xe2x80x2-diphosphate-dimyristoylglycerol with its antiviral action is known from Antimicrob. Agent. Chemother. 36, 2025 (1992).
Some of the derivatives described in this application are included in the patent document WO 91/19726 (PCT/US91/04289) and U.S. Pat. No. 4,622,392, but their description is very speculative and they do not contain any concrete details on the production of the compounds described in this application. Furthermore the compounds described in this application surprisingly have advantageous properties with regard to their pharmacological action which distinguishes them from the compounds described in the above-mentioned patent documents.
The compounds of the present invention are new and have valuable pharmacological properties. In particular they are suitable for the therapy and prophylaxis of infections which are caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegaly virus, papilloma virus, the Varicella-Zoster virus or Epstein-Barr virus or RNA viruses such as Toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II as well as the lentiviruses visna and human immune deficiency virus HIV-1 and 2.
The compounds of formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans such as persistent generalized lymphoadenopathy (PGL), the advanced stage of the AIDS-related complex and the full clinical picture of AIDS.
In addition the compounds of formula I are suitable for the therapy and prophylaxis of malignant tumours such as malignomas and neoplasias (carcinomas, sarcomas, leukaemia etc.) in tumour therapy as well as for the inhibition of oncogenic viruses.
In general the compound of formula I are then of interest when the coupled nucleoside (Nuc) has for example a cytotoxic, antitumoural, antiviral, anti-retroviral, immunosuppressive or immunostimulating action and cannot be used or only to a limited extent as a pharmaceutical agent because of side-effects, a too narrow therapeutic range or organ toxicities.
In comparison to the nucleosides that have been previously used for treatment, the compounds according to the invention have a low toxicity. They therefore have the advantage that pharmaceutical preparations that contain these compounds can be administered continuously over a long time period and it is possible to avoid discontinuation of the preparation or an intermittent administration as a result of undesired side-effects.